Hereditary Hemorrhagic Telangiectasia (HHT)

Overview

• Hereditary hemorrhagic telangiectasia (HHT), also called Osler-Weber-Rendu disease: the second-most common hereditary bleeding disorder (~1 in 5,000), and genuinely common.
• Autosomal dominant: many family members are typically affected.
• Characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs) that are fragile and bleed.
• Often diagnosed in adulthood; >90% have recurrent bleeding, mainly epistaxis (mild to transfusion-dependent), with GI bleeding in a minority, usually after age 50.

Pathophysiology and genetics

• Mutations in the TGF-β signaling pathway (ENG, ACVRL1) → ↑↑ VEGF signaling → ↑↑ angiogenesis → fragile, abnormal blood vessels (telangiectasias and AVMs) in the mouth, GI tract, and GU tract → bleeding.
• ENG (endoglin) = HHT type 1; associated with more pulmonary and cerebral AVMs.
• ACVRL1 (ALK1) = HHT type 2; associated with more hepatic AVMs, often later onset.
• SMAD4: combined juvenile polyposis-HHT overlap syndrome (screen for colonic polyps).

Diagnosis: Curacao criteria

• Diagnosis is clinical (Curacao criteria) supported by genetic testing.

• Interpretation (standard Curacao scoring): definite if ≥3 criteria; possible or suspected if 2; unlikely if <2.

Visceral AVMs by organ

• Most patients have visceral AVMs (lung, liver, brain) that may hemorrhage (potentially fatal) or cause high-output cardiac failure.

Management of bleeding

• Anemia: iron infusions and red cell transfusions.
• Antifibrinolytics: tranexamic acid (TXA), aminocaproic acid (EACA).
• Local ablative procedures: laser cautery, sclerotherapy, argon plasma coagulation.
• Antiangiogenic therapy: IV bevacizumab (anti-VEGF); oral thalidomide (and related agents).
• Refractory epistaxis: septodermoplasty; nasal closure (Young procedure).
• Epistaxis general measures: humidification and topical care; give indicated antiplatelet/anticoagulant therapy with individualized bleeding-risk management; avoid unnecessary, dual, or combined antithrombotic therapy where possible.

Heyde syndrome

• Triad: aortic stenosis + bleeding GI vascular lesions (angiodysplasia) + acquired von Willebrand syndrome.
• Mechanism: high shear across the stenotic aortic valve unfolds von Willebrand factor, exposing it to ADAMTS13 cleavage → loss of high-molecular-weight vWF multimers (acquired von Willebrand syndrome, type 2A pattern) → bleeding from GI angiodysplasia.
• Clinical clue: suspect on history; the aortic stenosis may not yet be known.
• Treatment: aortic valve replacement often (but not always) resolves the bleeding. Supportive care for bleeding: antifibrinolytics, octreotide.
• Related concept: vWF plays a physiologic role in angiogenesis, so vWF deficiency causes vascular lesions (most commonly GI angiodysplasia). Classically seen in type 2A vWD but can occur in other types; supportive treatment (antifibrinolytics, octreotide) is standard.

High yield

• HHT (Osler-Weber-Rendu): autosomal dominant, ENG and ACVRL1 (TGF-β pathway); epistaxis + telangiectases + visceral AVMs + family history.
• Curacao criteria: definite if ≥3 of 4.
• Pulmonary AVM: paradoxical emboli (stroke, brain abscess); screen with bubble echo, treat with embolization, give endocarditis-style antibiotic prophylaxis.
• Hepatic AVM: high-output cardiac failure; avoid biopsy; consider bevacizumab.
• Bleeding therapy: iron, antifibrinolytics, ablation, IV bevacizumab, thalidomide; nasal closure for refractory epistaxis.
• Heyde syndrome: aortic stenosis + GI angiodysplasia + acquired vWD (loss of HMW multimers); aortic valve replacement often cures the bleeding.